Compositions and methods for the treatment of neuromuscular disorders and neurodegenerative diseases

ABSTRACT

The invention relates to the compound of 
                         
or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for treating or preventing neuromuscular disorders and neurodegenerative diseases may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, or parenteral-administration, or syrup, or injection. Such compositions may be used to treatment or management of neuromuscular disorders and neurodegenerative diseases such as Parkinson&#39;s disease, scleroderma, restless leg syndrome, hypertension and gestational hypertension.

PRIORITY

This application is a national phase filing of the Patent CooperationTreaty (PCT) application # PCT/IB2013/052239 titled “COMPOSITIONS ANDMETHODS FOR THE TREATMENT OF NEUROMUSCULAR DISORDERS ANDNEURODEGENERATIVE DISEASES” filed on Mar. 21, 2013 Published with WIPOPublication # WO/2013/168021, which further claims priority to parentapplication 1779/CHE/2012 filed on May 7, 2012 in the country of India.The entire disclosure of the priority applications are relied on for allpurposes and is incorporated into this application by reference.

FIELD OF THE INVENTION

This disclosure generally relates to compounds and compositions for thetreatment of neuromuscular disorders, metabolic condition andneurodegenerative diseases. More particularly, this invention relates totreating subjects with a pharmaceutically acceptable dose of compounds,crystals, solvates, enantiomer or stereoisomer, esters, salts, hydrates,prodrugs, or mixtures thereof.

BACKGROUND OF THE INVENTION

Intercellular communication in the central nervous system requires theprecise control of the duration and the intensity of neurotransmitteraction at specific molecular targets. Plasma membrane neurotransmittertransporters are responsible for the high-affinity uptake ofneurotransmitters by neurons and glial cells at the level of theirplasma membrane.

Parkinson's disease (PD) is a neurodegenerative disorder that ischaracterized, in part, by a progressive loss of dopaminergic neurons inthe substantia nigra pars compacta. It affects 1.5% of the globalpopulation over 65 years of age. The lack of dopamine causes theclassical motor symptoms of bradykinesia, rigidity and resting tremors.These symptoms are improved by current dopamine replacement strategies,which include levodopa (1-DOPA, the precursor of dopamine) and dopaminereceptor agonists, as well as monoamine oxidase B (MAOB) inhibitors andcatechol O-methyltransferase inhibitors.

Current therapeutic development in PD includes approaches such asre-formulations (for example, extended release formulation) of existingdrugs that are approved for PD, re-positioning of compounds that areapproved for other indications (such as the antihypertensive drugisradipine, the antiepileptic topiramate or methylphenidate) anddevelopment of novel small-molecule and gene therapy-based approaches.The therapeutic development pipelines appear to be vigorous on thesurface. However, once dopaminergic compounds are removed from thedevelopment pipeline, the current landscape is far less encouraging.Such dopaminergic therapies include new formulations of existing drugs,which are more likely to provide incremental rather than profoundimprovements over existing therapies.

Many of the therapies that are currently under development—includingboth dopaminergic and non-dopaminergic compounds—are focused onimprovement of motor control, fluctuations and dyskinesias. Far fewerapproaches address the other two key unmet clinical needs, specifically:alleviating non-motor symptoms; and disease modification and/orneuroprotection.

Neurodegenerative disorders are a heterogeneous group of diseases of thenervous system, including the brain, spinal cord, and peripheral nervesthat have much different aetiology. Many are hereditary; some aresecondary to toxic or metabolic processes. Free radicals are highlyreactive molecules or chemical species capable of independent existence.Generation of highly Reactive Oxygen Species (ROS) is an integralfeature of normal cellular function like mitochondrial respiratorychain, phagocytosis and arachidonic acid metabolism. The release ofoxygen free radicals has also been reported during the recovery phasesfrom many pathological noxious stimuli to the cerebral tissues. Some ofthe neurodegenerative disorders include Alzheimer's disease,Huntington's disease, Parkinson's disease and Lateral sclerosis.

Managing acute pathology of often relies on the addressing underlyingpathology and symptoms of the disease. There is currently a need in theart for new compositions to treatment of neuromuscular disorders andneurodegenerative diseases.

SUMMARY OF THE INVENTION

The present invention provides compounds, compositions containing thesecompounds and methods for using the same to treat, prevent and/orameliorate the effects of the conditions such as neuromuscular disordersand neurodegenerative diseases.

The invention herein provides compositions comprising of formula I orpharmaceutical acceptable salts thereof. The invention also providespharmaceutical compositions comprising one or more compounds of formulaI or intermediates thereof and one or more of pharmaceuticallyacceptable carriers, vehicles or diluents. These compositions may beused in the treatment of neuromuscular disorders and neurodegenerativediseases and its associated complications.

In certain embodiments, the present invention relates to the compoundsand compositions of formula I, or pharmaceutically acceptable saltsthereof,

Wherein,R¹, R² each independently represents hydrogen, D, hydroxyl, methyl,amine, cycohexyl methyl ether, butoxy, propoxy, thiol, alkyl, alkylthiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl,alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl,aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl,heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl;R³ independently represents hydrogen, D, alkyl, methyl, ethyl, carboxyl,amine or thiol;R⁴ independently represents null, D, hydrogen, alkyl, carboxyl, amine,thiol, amine, cycohexyl methyl ether, butoxy, propoxy, thiol, alkyl,alkyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl,alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl,aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl,heterocyclyl, lower alkyl, sulfone, sulfoxide, hydroxyalkyl,—NH—CO—CH₂—NH—, —NH—CO—, R—COO—R¹, thiol, or2-amino-3-hydroxy-N-methylpropanamide;R⁵ independently represents null, hydrogen, alkyl, methyl, ethyl,carboxyl, amine, thiol, amine, cycohexyl methyl ether, butoxy, propoxy,thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acylalkyl,alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl,aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester,heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, hydroxyalkyl,—NH—CO—CH₂—NH—, —NH—CO—, R—COO—R¹, thiol, —NH₂—NH₂—, hydrazine,2-amino-3-hydroxy-N-methylpropanamide,

R⁶ independently represents null, hydrogen, alkyl, methyl, ethyl,carboxyl, —NH—CO—NH—, amine, cycohexyl methyl ether, butoxy, propoxy,thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acylalkyl,alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl,aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester,heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, hydroxyalkyl,—NH—CO—CH₂—NH—, —NH—CO—, R—COO—R¹, thiol,

or 2-amino-3-hydroxy-N-methylpropanamide;R⁷, R⁹ each independently represents H, D,

R⁸, R¹⁰ each independently represents,

a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃.

In the illustrative embodiments, examples of compounds of formula I areas set forth below:

Herein the application also provides a kit comprising any of thepharmaceutical compositions disclosed herein. The kit may compriseinstructions for use in the treatment of neuromuscular disorders andneurodegenerative diseases or its related complications.

The application also discloses a pharmaceutical composition comprising apharmaceutically acceptable carrier and any of the compositions herein.In some aspects, the pharmaceutical composition is formulated forsystemic administration, oral administration, sustained release,parenteral administration, injection, subdermal administration, ortransdermal administration.

Herein, the application additionally provides kits comprising thepharmaceutical compositions described herein. The kits may furthercomprise instructions for use in the treatment of neuromusculardisorders and neurodegenerative diseases or its related complications.

The compositions described herein have several uses. The presentapplication provides, for example, methods of treating a patientsuffering from neuromuscular disorders and neurodegenerative diseases orits related complications manifested from metabolic conditions, chronicdiseases or disorders; Hepatology, Hematological, Orthopedic,Cardiovascular, Renal, Skin, Neurological or Ocular complications.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the following terms and phrases shall have the meaningsset forth below. Unless defined otherwise, all technical and scientificterms used herein have the same meaning as commonly understood to one ofordinary skill in the art.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, andcycloalkyl-substituted alkyl groups. In preferred embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms inits backbone (e.g., C1-C30 for straight chains, C3-C30 for branchedchains), and more preferably 20 or fewer. Likewise, preferredcycloalkyls have from 3-10 carbon atoms in their ring structure, andmore preferably have 5, 6 or 7 carbons in the ring structure.

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms. Examples of alkyl groups include, but are not limited to, methyl(Me, —CH3), ethyl (Et, —CH2CH3), 1-propyl (n-Pr, n-propyl, —CH2CH2CH3),2-propyl (i-Pr, i-propyl, —CH(CH3)2), 1-butyl (n-Bu, n-butyl,—CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, —CH2CH(CH3)2), 2-butyl(s-Bu, s-butyl, —CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl,—C(CH3)3), 1-pentyl (n-pentyl, —CH2CH2CH2CH2CH3), 2-pentyl(—CH(CH3)CH2CH2CH3), 3-pentyl (—CH(CH2CH3)2), 2-methyl-2-butyl(—C(CH3)2CH2CH3), 3-methyl-2-butyl (—CH(CH3)CH(CH3)2), 3-methyl-1-butyl(—CH2CH2CH(CH3)2), 2-methyl-1-butyl (—CH2CH(CH3)CH2CH3), 1-hexyl(—CH2CH2CH2CH2CH2CH3), 2-hexyl (—CH(CH3)CH2CH2CH2 CH3), 3-hexyl(—CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (—C(CH3)2CH2CH2CH3),3-methyl-2-pentyl (—CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl(—CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (—C(CH3)(CH2CH3)2),2-methyl-3-pentyl (—CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl(—C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (—CH(CH3)C(CH3)3,1-heptyl,1-octyl, and the like.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to twelve carbon atoms with at least one siteof unsaturation, i.e., a carbon-carbon, sp double bond, wherein thealkenyl radical includes radicals having “cis” and “trans” orientations,or alternatively, “E” and “Z” orientations. Examples include, but arenot limited to, ethylenyl or vinyl (—CH═CH2), allyl (—CH2CH═CH2), andthe like. The term “alkynyl” refers to a linear or branched monovalenthydrocarbon radical of two to twelve carbon atoms with at least one siteof unsaturation, i.e., a carbon-carbon, sp triple bond. Examplesinclude, but are not limited to, ethynyl (—C≡CH), propynyl (propargyl,—CH2≡CH), and the like.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing a hydrogen on oneor more carbons of the hydrocarbon backbone. Such substituents, if nototherwise specified, can include, for example, a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl),a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, anamino, an amido, an amidine, an imine, a cyano, a nitro, an azido, asulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, asulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic orheteroaromatic moiety. It will be understood by those skilled in the artthat the moieties substituted on the hydrocarbon chain can themselves besubstituted, if appropriate. For instance, the substituents of asubstituted alkyl may include substituted and unsubstituted forms ofamino, azido, imino, amido, phosphoryl (including phosphonate andphosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl andsulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls(including ketones, aldehydes, carboxylates, and esters), —CF3, —CN andthe like. Exemplary substituted alkyls are described below. Cycloalkylscan be further substituted with alkyls, alkenyls, alkoxys, alkylthios,aminoalkyls, carbonyl-substituted alkyls, —CF3, —CN, and the like.

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbylC(O)—, preferably alkylC(O)—.

“Aryl” means a monocyclic or polycyclic ring assembly wherein each ringis aromatic or when fused with one or more rings forms an aromatic ringassembly. If one or more ring atoms is not carbon (e.g., N, S), the arylis a heteroaryl. Cx aryl and Cx-Y aryl are typically used where X and Yindicate the number of carbon atoms in the ring.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbyl C(O)NH—.

The term “acylalkyl” is art-recognized and refers to an alkyl groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbyl C(O)alkyl.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group, preferably a lower alkylgroup, having an oxygen attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond and is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds.

Moreover, such substituents include all those contemplated for alkylgroups, as discussed below, except where stability is prohibitive. Forexample, substitution of alkenyl groups by one or more alkyl,carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkylS—.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing a hydrogen onone or more carbons of the alkynyl group. Such substituents may occur onone or more carbons that are included or not included in one or moretriple bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed above, except where stability isprohibitive. For example, substitution of alkynyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a hetaryl group.

The term “heteroalkyl”, as used herein, refers to a saturated orunsaturated chain of carbon atoms and at least one heteroatom, whereinno two heteroatoms are adjacent.

The terms “heteroaryl” and “hetaryl” include substituted orunsubstituted aromatic single ring structures, preferably 5- to7-membered rings, more preferably 5- to 6-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and “hetaryl” also include polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings wherein at least one of the rings is heteroaromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroarylgroups include, for example, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, andpyrimidine, and the like.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, andsulfur.

The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer tosubstituted or unsubstituted non-aromatic ring structures, preferably 3-to 10-membered rings, more preferably 3- to 7-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heterocyclyl” and “heterocyclic” also include polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings isheterocyclic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.Heterocyclyl groups include, for example, piperidine, piperazine,pyrrolidine, morpholine, lactones, lactams, and the like.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group.

The term “lower” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups where there are ten or fewer non-hydrogen atoms in thesubstituent, preferably six or fewer. A “lower alkyl”, for example,refers to an alkyl group that contains ten or fewer carbon atoms,preferably six or fewer. Lower alkyls include methyl and ethyl. Incertain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxysubstituents defined herein are respectively lower acyl, lower acyloxy,lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether theyappear alone or in combination with other substituents, such as in therecitations hydroxyalkyl and aralkyl (in which case, for example, theatoms within the aryl group are not counted when counting the carbonatoms in the alkyl substituent).

The term “substituted” refers to moieties having substituents replacinghydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes the implicit provisothat such substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and non-aromaticsubstituents of organic compounds. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this application, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. Substituents can include any substituents described herein,for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate.

Unless specifically stated as “unsubstituted,” references to chemicalmoieties herein are understood to include substituted variants. Forexample, reference to an “aryl” group or moiety implicitly includes bothsubstituted and unsubstituted variants.

“Substituted or unsubstituted” means that a given moiety may consist ofonly hydrogen substituents through available valencies (unsubstituted)or may further comprise one or more non-hydrogen substituents throughavailable valencies (substituted) that are not otherwise specified bythe name of the given moiety. For example, isopropyl is an example of anethylene moiety that is substituted by —CH3. In general, a non-hydrogensubstituent may be any substituent that may be bound to an atom of thegiven moiety that is specified to be substituted. Examples ofsubstituents include, but are not limited to, aldehyde, alicyclic,aliphatic, (Ci-io) alkyl, alkylene, alkylidene, amide, amino,aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl,carbocyclyl, carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester,halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl,heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone,nitro, oxaalkyl and oxoalkyl moieties, each of which may optionally alsobe substituted or unsubstituted. In one particular embodiment, examplesof substituents include, but are not limited to, hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (Ci_io) alkoxy, (C4-12) aryloxy,hetero (Ci-io)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(Ci-10) alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-10)alkyl, halo (Ci-10) alkyl, hydroxy (Ci-10) alkyl, carbonyl (Ci-10)alkyl, thiocarbonyl (Ci_10) alkyl, sulfonyl (Ci-10) alkyl, sulfinyl(Ci_io) alkyl, (Ci_10) azaalkyl, imino (Ci-10) alkyl, (C3-12) cycloalkyl(C1-5) alkyl, hetero (C3-12) cycloalkyl (Ci-I0) alkyl, aryl (Ci-I0)alkyl, hetero (Ci-10) aryl (C1-5) alkyl, (C9-12) bicycloaryl (Ci_s)alkyl, hetero (Ce-I2) bicycloaryl (Ci_5) alkyl, (C3-12) cycloalkyl,hetero (C3-12) cycloalkyl, (C9-12) bicycloalkyl, hetero (C3-I2)bicycloalkyl, (C4-I2) aryl, hetero (Ci-10) aryl, (C9-12) bicycloaryl andhetero (C4-12) bicycloaryl. In addition, the substituent is itselfoptionally substituted by a further substituent. In one particularembodiment, examples of the further substituent include, but are notlimited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (Ci-10) alkoxy, (C4-I2) aryloxy, hetero (Ci-10) aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, (Ci-10) alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (Ci-10) alkyl, halo (Ci-10)alkyl, hydroxy (Ci-10) alkyl, carbonyl (Ci-10) alkyl, thiocarbonyl(Ci-10) alkyl, sulfonyl (Ci-10) alkyl, sulfinyl (Ci-10) alkyl, (Ci-10)azaalkyl, imino (Ci_io) alkyl, (C3-I2) cycloalkyl (Ci-5) alkyl, hetero(C3-12) cycloalkyl (Ci-10) alkyl, aryl (Ci_10) alkyl, hetero (Ci-io)aryl (Ci_5) alkyl, (C9-I2) bicycloaryl (C1-5) alkyl, hetero (C8-12)bicycloaryl (Ci_s) alkyl, (C3-12) cycloalkyl, hetero (C3_12) cycloalkyl,(C9-12) bicycloalkyl, hetero (C3-12) bicycloalkyl, (C4-12) aryl, hetero(Ci-10) aryl, (C9-12) bicycloaryl and hetero (C4-12) bicycloaryl.

The compounds of the present invention can be present in the form ofpharmaceutically acceptable salts. The compounds of the presentinvention can also be present in the form of pharmaceutically acceptableesters (i.e., the methyl and ethyl esters of the acids of formula I tobe used as prodrugs). The compounds of the present invention can also besolvated, i.e. hydrated. The solvation can be affected in the course ofthe manufacturing process or can take place i.e. as a consequence ofhygroscopic properties of an initially anhydrous compound of formula I(hydration).

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers.” Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers.” Diastereomers arestereoisomers with opposite configuration at one or more chiral centerswhich are not enantiomers. Stereoisomers bearing one or more asymmetriccenters that are non-superimposable mirror images of each other aretermed “enantiomers.” When a compound has an asymmetric center, forexample, if a carbon atom is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center or centers and isdescribed by the R- and S-sequencing rules of Cahn, lngold and Prelog,or by the manner in which the molecule rotates the plane of polarizedlight and designated as dextrorotatory or levorotatory (i.e., as (+) or(−)-isomers respectively). A chiral compound can exist as eitherindividual enantiomer or as a mixture thereof. A mixture containingequal proportions of the enantiomers is called a “racemic mixture”.

As used herein, the term “metabolic condition” refers to an Inbornerrors of metabolism (or genetic metabolic conditions) are geneticdisorders that result from a defect in one or more metabolic pathways;specifically, the function of an enzyme is affected and is eitherdeficient or completely absent.

In some embodiments, a molecular conjugate comprises of compoundsselected from the group consisting of R-lipoic acid (CAS No. 1200-22-2),salsalate (CAS No. 552-94-3), acetylcysteine (CAS No. 616-91-1),Eicosapentaenoic acid (CAS No. 10417-94-4), Docosahexaenoic acid (CASNo. 6217-54-5).

The term “polymorph” as used herein is art-recognized and refers to onecrystal structure of a given compound.

The phrases “parenteral administration” and “administered parenterally”as used herein refer to modes of administration other than enteral andtopical administration, such as injections, and include withoutlimitation intravenous, intramuscular, intrapleural, intravascular,intrapericardial, intraarterial, intrathecal, intracapsular,intraorbital, intracardiac, intradennal, intraperitoneal, transtracheal,subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid,intraspinal and intrastemal injection and infusion.

A “patient,” “subject,” or “host” to be treated by the subject methodmay mean either a human or non-human animal, such as primates, mammals,and vertebrates.

The phrase “pharmaceutically acceptable” is art-recognized. In certainembodiments, the term includes compositions, polymers and othermaterials and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues ofmammals, human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” is art-recognized, andincludes, for example, pharmaceutically acceptable materials,compositions or vehicles, such as a liquid or solid filler, diluent,solvent or encapsulating material involved in carrying or transportingany subject composition, from one organ, or portion of the body, toanother organ, or portion of the body. Each carrier must be “acceptable”in the sense of being compatible with the other ingredients of a subjectcomposition and not injurious to the patient. In certain embodiments, apharmaceutically acceptable carrier is non-pyrogenic. Some examples ofmaterials which may serve as pharmaceutically acceptable carriersinclude: (1) sugars, such as lactose, glucose and sucrose; (2) starches,such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

The term “prodrug” is intended to encompass compounds that, underphysiological conditions, are converted into the therapeutically activeagents of the present invention. A common method for making a prodrug isto include selected moieties that are hydrolyzed under physiologicalconditions to reveal the desired molecule. In other embodiments, theprodrug is converted by an enzymatic activity of the host animal.

The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic, i.e., it protects thehost against developing the unwanted condition, whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic, (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The term “predicting” as used herein refers to assessing the probabilityrelated diseases patient will suffer from abnormalities or complicationand/or terminal platelet aggregation or failure and/or death (i.e.mortality) within a defined time window (predictive window) in thefuture. The mortality may be caused by the central nervous system orcomplication. The predictive window is an interval in which the subjectwill develop one or more of the said complications according to thepredicted probability. The predictive window may be the entire remaininglifespan of the subject upon analysis by the method of the presentinvention.

The term “treating” is art-recognized and includes preventing a disease,disorder or condition from occurring in an animal which may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it; inhibiting the disease, disorder orcondition, e.g., impeding its progress; and relieving the disease,disorder, or condition, e.g., causing regression of the disease,disorder and/or condition. Treating the disease or condition includesameliorating at least one symptom of the particular disease orcondition, even if the underlying pathophysiology is not affected, suchas treating or management of Parkinson's disease, scleroderma, restlessleg syndrome, hypertension and gestational hypertension of a subject byadministration of an agent even though such agent does not treat thecause of the condition. The term “treating”, “treat” or “treatment” asused herein includes curative, preventative (e.g., prophylactic),adjunct and palliative treatment.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a salt orcomposition disclosed herein that produces some desired effect at areasonable benefit/risk ratio applicable to any medical treatment. Incertain embodiments, the term refers to that amount necessary orsufficient to eliminate or reduce medical symptoms for a period of time.The effective amount may vary depending on such factors as the diseaseor condition being treated, the particular targeted constructs beingadministered, the size of the subject, or the severity of the disease orcondition. One of ordinary skill in the art may empirically determinethe effective amount of a particular composition without necessitatingundue experimentation.

In certain embodiments, the pharmaceutical compositions described hereinare formulated in a manner such that said compositions will be deliveredto a patient in a therapeutically effective amount, as part of aprophylactic or therapeutic treatment. The desired amount of thecomposition to be administered to a patient will depend on absorption,inactivation, and excretion rates of the drug as well as the deliveryrate of the salts and compositions from the subject compositions. It isto be noted that dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions. Typically, dosing will be determined using techniquesknown to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular salt or composition may be adjusted to accommodatevariations in the treatment parameters. Such treatment parametersinclude the clinical use to which the preparation is put, e.g., the sitetreated, the type of patient, e.g., human or non-human, adult or child,and the nature of the disease or condition.

In certain embodiments, the dosage of the subject compositions providedherein may be determined by reference to the plasma concentrations ofthe therapeutic composition or other encapsulated materials. Forexample, the maximum plasma concentration (Cmax) and the area under theplasma concentration-time curve from time 0 to infinity may be used.

When used with respect to a pharmaceutical composition or othermaterial, the term “sustained release” is art-recognized. For example, asubject composition which releases a substance over time may exhibitsustained release characteristics, in contrast to a bolus typeadministration in which the entire amount of the substance is madebiologically available at one time. For example, in particularembodiments, upon contact with body fluids including blood, spinalfluid, mucus secretions, lymph or the like, one or more of thepharmaceutically acceptable excipients may undergo gradual or delayeddegradation (e.g., through hydrolysis) with concomitant release of anymaterial incorporated therein, e.g., an therapeutic and/or biologicallyactive salt and/or composition, for a sustained or extended period (ascompared to the release from a bolus). This release may result inprolonged delivery of therapeutically effective amounts of any of thetherapeutic agents disclosed herein.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” areart-recognized, and include the administration of a subject composition,therapeutic or other material at a site remote from the disease beingtreated. Administration of an agent for the disease being treated, evenif the agent is subsequently distributed systemically, may be termed“local” or “topical” or “regional” administration, other than directlyinto the central nervous system, e.g., by subcutaneous administration,such that it enters the patient's system and, thus, is subject tometabolism and other like processes.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a salt orcomposition disclosed herein that produces some desired effect at areasonable benefit/risk ratio applicable to any medical treatment. Incertain embodiments, the term refers to that amount necessary orsufficient to eliminate or reduce medical symptoms for a period of time.The effective amount may vary depending on such factors as the diseaseor condition being treated, the particular targeted constructs beingadministered, the size of the subject, or the severity of the disease orcondition. One of ordinary skill in the art may empirically determinethe effective amount of a particular composition without necessitatingundue experimentation.

The present disclosure also contemplates prodrugs of the compositionsdisclosed herein, as well as pharmaceutically acceptable salts of saidprodrugs.

This application also discloses a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and the composition of a compoundof Formula I may be formulated for systemic or topical or oraladministration. The pharmaceutical composition may be also formulatedfor oral administration, oral solution, injection, subdermaladministration, or transdermal administration. The pharmaceuticalcomposition may further comprise at least one of a pharmaceuticallyacceptable stabilizer, diluent, surfactant, filler, binder, andlubricant.

In many embodiments, the pharmaceutical compositions described hereinwill incorporate the disclosed compounds and compositions (Formula I) tobe delivered in an amount sufficient to deliver to a patient atherapeutically effective amount of a compound of formula I orcomposition as part of a prophylactic or therapeutic treatment. Thedesired concentration of formula I or its pharmaceutical acceptablesalts will depend on absorption, inactivation, and excretion rates ofthe drug as well as the delivery rate of the salts and compositions fromthe subject compositions. It is to be noted that dosage values may alsovary with the severity of the condition to be alleviated. It is to befurther understood that for any particular subject, specific dosageregimens should be adjusted over time according to the individual needand the professional judgment of the person administering or supervisingthe administration of the compositions. Typically, dosing will bedetermined using techniques known to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular compound of formula I may be adjusted to accommodatevariations in the treatment parameters. Such treatment parametersinclude the clinical use to which the preparation is put, e.g., the sitetreated, the type of patient, e.g., human or non-human, adult or child,and the nature of the disease or condition.

The concentration and/or amount of any compound of formula I may bereadily identified by routine screening in animals, e.g., rats, byscreening a range of concentration and/or amounts of the material inquestion using appropriate assays. Known methods are also available toassay local tissue concentrations, diffusion rates of the salts orcompositions, and local blood flow before and after administration oftherapeutic formulations disclosed herein. One such method ismicrodialysis, as reviewed by T. E. Robinson et al., 1991, microdialysisin the neurosciences, Techniques, volume 7, Chapter 1. The methodsreviewed by Robinson may be applied, in brief, as follows. Amicrodialysis loop is placed in situ in a test animal. Dialysis fluid ispumped through the loop. When compounds with formula I such as thosedisclosed herein are injected adjacent to the loop, released drugs arecollected in the dialysate in proportion to their local tissueconcentrations. The progress of diffusion of the salts or compositionsmay be determined thereby with suitable calibration procedures usingknown concentrations of salts or compositions.

In certain embodiments, the dosage of the subject compounds of formula Iprovided herein may be determined by reference to the plasmaconcentrations of the therapeutic composition or other encapsulatedmaterials. For example, the maximum plasma concentration (Cmax) and thearea under the plasma concentration-time curve from time 0 to infinitymay be used.

Generally, in carrying out the methods detailed in this application, aneffective dosage for the compounds of Formulas I is in the range ofabout 0.01 mg/kg/day to about 100 mg/kg/day in single or divided doses,for instance 0.01 mg/kg/day to about 50 mg/kg/day in single or divideddoses. The compounds of Formulas I may be administered at a dose of, forexample, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day, 5mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day.Compounds of Formula I may also be administered to a human patient at adose of, for example, between 0.1 mg and 1000 mg, between 5 mg and 80mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500,800, 1000, 2000, 5000 mg per day. In certain embodiments, thecompositions herein are administered at an amount that is less than 95%,90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound offormula I required for the same therapeutic benefit.

An effective amount of the compounds of formula I described hereinrefers to the amount of one of said salts or compositions which iscapable of inhibiting or preventing a disease.

An effective amount may be sufficient to prohibit, treat, alleviate,ameliorate, halt, restrain, slow or reverse the progression, or reducethe severity of a complication resulting from nerve damage ordemyelization and/or elevated reactive oxidative-nitrosative speciesand/or abnormalities in physiological homeostasis's, in patients who areat risk for such complications. As such, these methods include bothmedical therapeutic (acute) and/or prophylactic (prevention)administration as appropriate. The amount and timing of compositionsadministered will, of course, be dependent on the subject being treated,on the severity of the affliction, on the manner of administration andon the judgment of the prescribing physician. Thus, because ofpatient-to-patient variability, the dosages given above are a guidelineand the physician may titrate doses of the drug to achieve the treatmentthat the physician considers appropriate for the patient. In consideringthe degree of treatment desired, the physician must balance a variety offactors such as age of the patient, presence of preexisting disease, aswell as presence of other diseases.

The compositions provided by this application may be administered to asubject in need of treatment by a variety of conventional routes ofadministration, including orally, topically, parenterally, e.g.,intravenously, subcutaneously or intramedullary. Further, thecompositions may be administered intranasally, as a rectal suppository,or using a “flash” formulation, i.e., allowing the medication todissolve in the mouth without the need to use water. Furthermore, thecompositions may be administered to a subject in need of treatment bycontrolled release dosage forms, site specific drug delivery,transdermal drug delivery, patch (active/passive) mediated drugdelivery, by stereotactic injection, or in nanoparticles.

The compositions may be administered alone or in combination withpharmaceutically acceptable carriers, vehicles or diluents, in eithersingle or multiple doses. Suitable pharmaceutical carriers, vehicles anddiluents include inert solid diluents or fillers, sterile aqueoussolutions and various organic solvents. The pharmaceutical compositionsformed by combining the compositions and the pharmaceutically acceptablecarriers, vehicles or diluents are then readily administered in avariety of dosage forms such as tablets, powders, lozenges, syrups,injectable solutions and the like. These pharmaceutical compositionscan, if desired, contain additional ingredients such as flavorings,binders, excipients and the like. Thus, for purposes of oraladministration, tablets containing various excipients such asL-arginine, sodium citrate, calcium carbonate and calcium phosphate maybe employed along with various disintegrates such as starch, alginicacid and certain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard filledgelatin capsules. Appropriate materials for this include lactose or milksugar and high molecular weight polyethylene glycols. When aqueoussuspensions or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if desired,emulsifying or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin and combinations thereof. Thecompounds of formula I may also comprise enterically coated comprisingof various excipients, as is well known in the pharmaceutical art.

For parenteral administration, solutions of the compositions may beprepared in (for example) sesame or peanut oil, aqueous propyleneglycol, or in sterile aqueous solutions may be employed. Such aqueoussolutions should be suitably buffered if necessary and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theseparticular aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. In thisconnection, the sterile aqueous media employed are all readily availableby standard techniques known to those skilled in the art.

The formulations, for instance tablets, may contain e.g. 10 to 100, 50to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700,800 mg of the compounds of formula I disclosed herein, for instance,compounds of formula I or pharmaceutical acceptable salts of a compoundsof Formula I.

Generally, a composition as described herein may be administered orally,or parenterally (e.g., intravenous, intramuscular, subcutaneous orintramedullary). Topical administration may also be indicated, forexample, where the patient is suffering from gastrointestinal disorderthat prevent oral administration, or whenever the medication is bestapplied to the surface of a tissue or organ as determined by theattending physician. Localized administration may also be indicated, forexample, when a high dose is desired at the target tissue or organ. Forbuccal administration the active composition may take the form oftablets or lozenges formulated in a conventional manner.

The dosage administered will be dependent upon the identity of themetabolic disease; the type of host involved, including its age, healthand weight; the kind of concurrent treatment, if any; the frequency oftreatment and therapeutic ratio.

Illustratively, dosage levels of the administered active ingredientsare: intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500mg/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 toabout 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host bodyweight.

Expressed in terms of concentration, an active ingredient can be presentin the compositions of the present invention for localized use about thecutis, intranasally, pharyngolaryngeally, bronchially, intravaginally,rectally, or ocularly in a concentration of from about 0.01 to about 50%w/w of the composition; preferably about 1 to about 20% w/w of thecomposition; and for parenteral use in a concentration of from about0.05 to about 50% w/v of the composition and preferably from about 5 toabout 20% w/v.

The compositions of the present invention are preferably presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, suppositories, sterileparenteral solutions or suspensions, sterile non-parenteral solutions ofsuspensions, and oral solutions or suspensions and the like, containingsuitable quantities of an active ingredient. For oral administrationeither solid or fluid unit dosage forms can be prepared.

As discussed above, the tablet core contains one or more hydrophilicpolymers. Suitable hydrophilic polymers include, but are not limited to,water swellable cellulose derivatives, polyalkylene glycols,thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids,clays, gelling starches, swelling cross-linked polymers, and mixturesthereof. Examples of suitable water swellable cellulose derivativesinclude, but are not limited to, sodium carboxymethylcellulose,cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, andmixtures thereof. Examples of suitable polyalkylene glycols include, butare not limited to, polyethylene glycol. Examples of suitablethermoplastic polyalkylene oxides include, but are not limited to,poly(ethylene oxide). Examples of suitable acrylic polymers include, butare not limited to, potassium methacrylatedivinylbenzene copolymer,polymethylmethacrylate, high-molecular weight crosslinked acrylic acidhomopolymers and copolymers such as those commercially available fromNoveon Chemicals under the tradename CARBOPOL™. Examples of suitablehydrocolloids include, but are not limited to, alginates, agar, guargum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gumarabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin,galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin,pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, and mixtures thereof. Examples of suitable claysinclude, but are not limited to, smectites such as bentonite, kaolin,and laponite; magnesium trisilicate; magnesium aluminum silicate; andmixtures thereof. Examples of suitable gelling starches include, but arenot limited to, acid hydrolyzed starches, swelling starches such assodium starch glycolate and derivatives thereof, and mixtures thereof.Examples of suitable swelling cross-linked polymers include, but are notlimited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, andcross-linked carboxymethylcellulose sodium, and mixtures thereof.

The carrier may contain one or more suitable excipients for theformulation of tablets. Examples of suitable excipients include, but arenot limited to, fillers, adsorbents, binders, disintegrants, lubricants,glidants, release-modifying excipients, superdisintegrants,antioxidants, and mixtures thereof.

Suitable binders include, but are not limited to, dry binders such aspolyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders suchas water-soluble polymers, including hydrocolloids such as acacia,alginates, agar, guar gum, locust bean, carrageenan,carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan,gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin,scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, andstarches; and mixtures thereof. Suitable disintegrants include, but arenot limited to, sodium starch glycolate, cross-linkedpolyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches,microcrystalline cellulose, and mixtures thereof.

Suitable lubricants include, but are not limited to, long chain fattyacids and their salts, such as magnesium stearate and stearic acid,talc, glycerides waxes, and mixtures thereof. Suitable glidants include,but are not limited to, colloidal silicon dioxide. Suitablerelease-modifying excipients include, but are not limited to, insolubleedible materials, pH-dependent polymers, and mixtures thereof.

Suitable insoluble edible materials for use as release-modifyingexcipients include, but are not limited to, water-insoluble polymers andlow-melting hydrophobic materials, copolymers thereof, and mixturesthereof. Examples of suitable water-insoluble polymers include, but arenot limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate,polycaprolactones, cellulose acetate and its derivatives, acrylates,methacrylates, acrylic acid copolymers, copolymers thereof, and mixturesthereof. Suitable low-melting hydrophobic materials include, but are notlimited to, fats, fatty acid esters, phospholipids, waxes, and mixturesthereof. Examples of suitable fats include, but are not limited to,hydrogenated vegetable oils such as for example cocoa butter,hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenatedsunflower oil, and hydrogenated soybean oil, free fatty acids and theirsalts, and mixtures thereof. Examples of suitable fatty acid estersinclude, but are not limited to, sucrose fatty acid esters, mono-, di-,and triglycerides, glyceryl behenate, glyceryl palmitostearate, glycerylmonostearate, glyceryl tristearate, glyceryl trilaurylate, glycerylmyristate, GlycoWax-932, lauroyl macrogol-32 glycerides, stearoylmacrogol-32 glycerides, and mixtures thereof. Examples of suitablephospholipids include phosphotidyl choline, phosphotidyl serene,phosphotidyl enositol, phosphotidic acid, and mixtures thereof. Examplesof suitable waxes include, but are not limited to, carnauba wax,spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystallinewax, and paraffin wax; fat-containing mixtures such as chocolate, andmixtures thereof. Examples of super disintegrants include, but are notlimited to, croscarmellose sodium, sodium starch glycolate andcross-linked povidone (crospovidone). In one embodiment the tablet corecontains up to about 5 percent by weight of such super disintegrant.

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.Examples of preservatives include, but are not limited to, citric acid,tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, andsorbic acid, and mixtures thereof.

In one embodiment, the immediate release coating has an averagethickness of at least 50 microns, such as from about 50 microns to about2500 microns; e.g., from about 250 microns to about 1000 microns. Inembodiment, the immediate release coating is typically compressed at adensity of more than about 0.9 g/cc, as measured by the weight andvolume of that specific layer.

In one embodiment, the immediate release coating contains a firstportion and a second portion, wherein at least one of the portionscontains the second pharmaceutically active agent. In one embodiment,the portions contact each other at a center axis of the tablet. In oneembodiment, the first portion includes the first pharmaceutically activeagent and the second portion includes the second pharmaceutically activeagent.

In one embodiment, the first portion contains the first pharmaceuticallyactive agent and the second portion contains the second pharmaceuticallyactive agent. In one embodiment, one of the portions contains a thirdpharmaceutically active agent. In one embodiment one of the portionscontains a second immediate release portion of the same pharmaceuticallyactive agent as that contained in the tablet core.

In one embodiment, the outer coating portion is prepared as a dry blendof materials prior to addition to the coated tablet core. In anotherembodiment the outer coating portion is included of a dried granulationincluding the pharmaceutically active agent.

Formulations with different drug release mechanisms described abovecould be combined in a final dosage form containing single or multipleunits. Examples of multiple units include multilayer tablets, capsulescontaining tablets, beads, or granules in a solid or liquid form.Typical, immediate release formulations include compressed tablets,gels, films, coatings, liquids and particles that can be encapsulated,for example, in a gelatin capsule. Many methods for preparing coatings,covering or incorporating drugs, are known in the art.

The immediate release dosage, unit of the dosage form, i.e., a tablet, aplurality of drug-containing beads, granules or particles, or an outerlayer of a coated core dosage form, contains a therapeutically effectivequantity of the active agent with conventional pharmaceuticalexcipients. The immediate release dosage unit may or may not be coated,and may or may not be admixed with the delayed release dosage unit orunits (as in an encapsulated mixture of immediate releasedrug-containing granules, particles or beads and delayed releasedrug-containing granules or beads).

Extended release formulations are generally prepared as diffusion orosmotic systems, for example, as described in “Remington—The Science andPractice of Pharmacy”, 20th. Ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000). A diffusion system typically consists of one oftwo types of devices, reservoir and matrix, which are wellknown anddescribed in die art. The matrix devices are generally prepared bycompressing the drug with a slowly dissolving polymer carrier into atablet form.

An immediate release portion can be added to the extended release systemby means of either applying an immediate release layer on top of theextended release core; using coating or compression processes or in amultiple unit system such as a capsule containing extended and immediaterelease beads.

Delayed release dosage formulations are created by coating a soliddosage form with a film of a polymer which is insoluble in the acidenvironment of the stomach, but soluble in the neutral environment ofsmall intestines. The delayed release dosage units can be prepared, forexample, by coating a drug or a drug-containing composition with aselected coating material. The drug-containing composition may be atablet for incorporation into a capsule, a tablet for use as an innercore in a “coated core” dosage form, or a plurality of drug-containingbeads, particles or granules, for incorporation into either a tablet orcapsule.

A pulsed release dosage form is one that mimics a multiple dosingprofile without repeated dosing and typically allows at least a twofoldreduction in dosing frequency as compared to the drug presented as aconventional dosage form (e.g., as a solution or prompt drug-releasing,conventional solid dosage form). A pulsed release profile ischaracterized by a time period of no release (lag time) or reducedrelease followed by rapid drug release.

Each dosage form contains a therapeutically effective amount of activeagent. In one embodiment of dosage forms that mimic a twice daily dosingprofile, approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60wt. %, of the total amount of active agent in the dosage form isreleased in the initial pulse, and, correspondingly approximately 70 wt.% to 3.0 wt. %, preferably 60 wt. % to 40 wt. %, of the total amount ofactive agent in the dosage form is released in the second pulse. Fordosage forms mimicking the twice daily dosing profile, the second pulseis preferably released approximately 3 hours to less than 14 hours, andmore preferably approximately 5 hours to 12 hours, followingadministration.

Another dosage form contains a compressed tablet or a capsule having adrug-containing immediate release dosage unit, a delayed release dosageunit and an optional second delayed release dosage unit. In this dosageform, the immediate release dosage unit contains a plurality of beads,granules particles that release drug substantially immediately followingoral administration to provide an initial dose. The delayed releasedosage unit contains a plurality of coated beads or granules, whichrelease drug approximately 3 hours to 14 hours following oraladministration to provide a second dose.

For purposes of transdermal (e.g., topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, may be prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of one or more compounds of formula I or other active agents areknown, or will be apparent in light of this disclosure, to those skilledin this art. For examples of methods of preparing pharmaceuticalcompositions, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 19th Edition (1995).

In addition, in certain embodiments, subject compositions of the presentapplication maybe lyophilized or subjected to another appropriate dryingtechnique such as spray drying. The subject compositions may beadministered once, or may be divided into a number of smaller doses tobe administered at varying intervals of time, depending in part on therelease rate of the compositions and the desired dosage.

Formulations useful in the methods provided herein include thosesuitable for oral, nasal, topical (including buccal and sublingual),rectal, vaginal, aerosol and/or parenteral administration. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any methods well known in the art of pharmacy. The amountof a subject composition which may be combined with a carrier materialto produce a single dose may vary depending upon the subject beingtreated, and the particular mode of administration.

Methods of preparing these formulations or compositions include the stepof bringing into association subject compositions with the carrier and,optionally, one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation a subject composition with liquid carriers, or finelydivided solid carriers, or both, and then, if necessary, shaping theproduct.

The compounds of formula I described herein may be administered ininhalant or aerosol formulations. The inhalant or aerosol formulationsmay comprise one or more agents, such as adjuvants, diagnostic agents,imaging agents, or therapeutic agents useful in inhalation therapy. Thefinal aerosol formulation may for example contain 0.005-90% w/w, forinstance 0.005-50%, 0.005-5% w/w, or 0.01-1.0% w/w, of medicamentrelative to the total weight of the formulation.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers and/or anyof the following: (1) fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as,for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol;(4) disintegrating agents, such as agar-agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain silicates, and sodiumcarbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, acetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-filled gelatin capsules using lactose or milk sugars, as wellas high molecular weight polyethylene glycols and the like.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the subject compositions, the liquid dosageforms may contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, corn, peanut, sunflower,soybean, olive, castor, and sesame oils), glycerol, tetrahydrofurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Suspensions, in addition to the subject compositions, may containsuspending agents such as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol, and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing a subject composition withone or more suitable non-irritating carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax, or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the appropriate body cavity and release theencapsulated compound(s) and composition(s). Formulations which aresuitable for vaginal administration also include pessaries, tampons,creams, gels, pastes, foams, or spray formulations containing suchcarriers as are known in the art to be appropriate.

Dosage forms for transdermal administration include powders, sprays,ointments, pastes, creams, lotions, gels, solutions, patches, andinhalants. A subject composition may be mixed under sterile conditionswith a pharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants that may be required. For transdermaladministration, the complexes may include lipophilic and hydrophilicgroups to achieve the desired water solubility and transport properties.

The ointments, pastes, creams and gels may contain, in addition tosubject compositions, other carriers, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof. Powders and sprays may contain, in additionto a subject composition, excipients such as lactose, talc, silicicacid, aluminum hydroxide, calcium silicates and polyamide powder, ormixtures of such substances. Sprays may additionally contain customarypropellants, such as chlorofluorohydrocarbons and volatile unsubstitutedhydrocarbons, such as butane and propane.

Methods of delivering a composition or compositions via a transdermalpatch are known in the art. Exemplary patches and methods of patchdelivery are described in U.S. Pat. Nos. 6,974,588, 6,564,093,6,312,716, 6,440,454, 6,267,983, 6,239,180, and 6,103,275.

In another embodiment, a transdermal patch may comprise: a substratesheet comprising a composite film formed of a resin compositioncomprising 100 parts by weight of a polyvinyl chloride-polyurethanecomposite and 2-10 parts by weight of astyrene-ethylene-butylene-styrene copolymer, a first adhesive layer onthe one side of the composite film, and a polyalkylene terephthalatefilm adhered to the one side of the composite film by means of the firstadhesive layer, a primer layer which comprises a saturated polyesterresin and is formed on the surface of the polyalkylene terephthalatefilm; and a second adhesive layer comprising a styrene-diene-styreneblock copolymer containing a pharmaceutical agent layered on the primerlayer. A method for the manufacture of the above-mentioned substratesheet comprises preparing the above resin composition molding the resincomposition into a composite film by a calendar process, and thenadhering a polyalkylene terephthalate film on one side of the compositefilm by means of an adhesive layer thereby forming the substrate sheet,and forming a primer layer comprising a saturated polyester resin on theouter surface of the polyalkylene terephthalate film.

Another type of patch comprises incorporating the drug directly in apharmaceutically acceptable adhesive and laminating the drug-containingadhesive onto a suitable backing member, e.g. a polyester backingmembrane. The drug should be present at a concentration which will notaffect the adhesive properties, and at the same time deliver therequired clinical dose.

Transdermal patches may be passive or active. Passive transdermal drugdelivery systems currently available, such as the nicotine, estrogen andnitroglycerine patches, deliver small-molecule drugs. Many of the newlydeveloped proteins and peptide drugs are too large to be deliveredthrough passive transdermal patches and may be delivered usingtechnology such as electrical assist (iontophoresis) for large-moleculedrugs.

Iontophoresis is a technique employed for enhancing the flux of ionizedsubstances through membranes by application of electric current. Oneexample of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646to Theeuwes. The principal mechanisms by which iontophoresis enhancesmolecular transport across the skin are (a) repelling a charged ion froman electrode of the same charge, (b) electroosmosis, the convectivemovement of solvent that occurs through a charged pore in response thepreferential passage of counter-ions when an electric field is appliedor (c) increase skin permeability due to application of electricalcurrent.

In some cases, it may be desirable to administer in the form of a kit,it may comprise a container for containing the separate compositionssuch as a divided bottle or a divided foil packet. Typically the kitcomprises directions for the administration of the separate components.The kit form is particularly advantageous when the separate componentsare preferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a plastic material that may betransparent.

Methods and compositions for the treatment of neuromuscular disordersand neurodegenerative diseases. Among other things, herein is provided amethod of treating neuromuscular disorders and neurodegenerativediseases, comprising administering to a patient in need thereof atherapeutically effective amount of compound of Formula I:

Wherein,R¹, R² each independently represents hydrogen, D, hydroxyl, methyl,amine, cycohexyl methyl ether, butoxy, propoxy, thiol, alkyl, alkylthiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl,alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl,aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl,heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl;R³ independently represents hydrogen, D, alkyl, methyl, ethyl, carboxyl,amine or thiol;R⁴ independently represents null, D, hydrogen, alkyl, carboxyl, amine,thiol, amine, cycohexyl methyl ether, butoxy, propoxy, thiol, alkyl,alkyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl,alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl,aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl,heterocyclyl, lower alkyl, sulfone, sulfoxide, hydroxyalkyl,—NH—CO—CH₂—NH—, —NH—CO—, R—COO—R¹, thiol, or2-amino-3-hydroxy-N-methylpropanamide;R⁵ independently represents null, hydrogen, alkyl, methyl, ethyl,carboxyl, amine, thiol, amine, cycohexyl methyl ether, butoxy, propoxy,thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acylalkyl,alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl,aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester,heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, hydroxyalkyl,—NH—CO—CH₂—NH—, —NH—CO—, R—COO—R¹, thiol, —NH₂—NH₂—, hydrazine,2-amino-3-hydroxy-N-methylpropanamide,

R⁶ independently represents null, hydrogen, alkyl, methyl, ethyl,carboxyl, —NH—CO—NH—, amine, cycohexyl methyl ether, butoxy, propoxy,thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acylalkyl,alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl,aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester,heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, hydroxyalkyl,—NH—CO—CH₂—NH—, —NH—CO—, R—COO—R¹, thiol,

or 2-amino-3-hydroxy-N-methylpropanamide;R⁷, R⁹ each independently represents H, D,

R⁸, R¹⁰ each independently represents,

a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃.Methods for Using Compounds of Formula I:

The invention also includes methods for treating or management ofParkinson's disease, scleroderma, restless leg syndrome, hypertensionand gestational hypertension.

Methods of Making

Methods for making the compounds of formula I are set forth as examplesbelow:

Example 1

Synthesis of Compound-2

To a solution of compound 1 (50 mmol) in 1:1 mixture of THF/H2O (300mL), NaHCO₃ (150 mmol) and Boc2O (110 mmol) were added consecutively at0° C. After 30 min, the solution was stirred overnight at roomtemperature. The turbid solution was extracted with Et2O (2×200 mL). Theaqueous layer was acidified to pH=4-5 by careful addition of half sat.citric acid at 0° C. and then extracted with CH2C12 (3×200 mL). Thecombined organic phase was dried (Na2SO4) and evaporated under reducedpressure to give the Boc-amino acids with high purity as solids or hardcolorless oils, which crystallize on standing. These Boc-amino acidswere used for next step without purification. M.F: C₂₀H₃₀N₂O₈; Mol. Wt.:426.46.

Synthesis of Compound-3

To a two-necked 500 mL flask were added compound 2 (50 mmol),2,2-dimethoxypropane (200 mmol), and anhydrous toluene (20 vol). Oneneck of the flask was fitted with a Soxhlet extractor, the thimble ofwhich was filled with granular anhydrous CaCl₂ (75 g) to trap MeOH andH₂O. The other neck of the flask was sealed with a septum for sampling.After the system was flushed with argon for 5 min and then heated toreflux for 5 min, p-toluenesulfonic acid monohydrate (430 mg, 4.5 mol %)was added & left refluxing for 12 h. Reaction mixture concentrated underreduced pressure. The reaction residue diluted with ethyl acetate (10Vol), washed with saturated sodium bi carbonate solution followed bybrine. The organic layer dried over sodium sulfate, filtered andconcentrated under vacuum yielded compound 3. M.F: C₂₃H₃₄N₂O₈; Mol. Wt.:466.52.

Synthesis of Compound-6

To a solution of compound 4 (1.0 mmol) in dry DCM (1.8 L) was added N,N-diisopropylethylamine (2.0 mmol) at −10° C., followed by drop wiseaddition of 1-chloroethylchloroformate (1.2 mmol) for 30 min at the sametemperature and the reaction mixture was allowed to stir for 1 h at 0°C. On completion of the reaction (monitored by TLC), the reactionmixture intermediate 5 was directly used for the next step withoutfurther isolation and purification. In another RB flask the cis-5, 8,11, 14, 17-Eicosapentaenoic acid (1.2 mmol) & anhydrous K₂CO₃ (3.0 mmol)was taken in dry DMF (10 vol) stir at room temperature for 2 h and thencooled to −10° C., intermediate 5 was added slowly drop wise over 30min. & then was allowed to stir at room temperature for 12 h. Reactionwas monitored by TLC. On completion of the reaction, the reactionmixture was poured into water (100 mL) and extracted with diethyl ether(2×1 L). The combined organic layers were washed with water (2×500 mL)followed by brine solution (100 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure. The crude was purified by columnchromatography over 100-200 mesh silica gel by using 0 to 20% ethylacetate in pet ether as an eluent yielded 40% of compound 6 as a yellowliquid. M.F: C₄₆H₆₆N₂O₁₂; Mol. Wt.: 839.02.

Synthesis of Compound-7

25% TFA in DCM was added to compound 6 (1.0 mmol) at 0° C. and thereaction mixture was allowed to stir for 30 min at the same temperature.Reaction was monitored by TLC. On completion of the reaction, thereaction mixture was basified with saturated Na₂CO₃ solution (20 vol)and extracted with DCM (20 vol), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure. The crude was purified by columnchromatography over neutral alumina (Merck) by using 30% ethylacetate-pet ether as eluent yielded 46% of compound 7 as a pale yellowgummy solid. M.F: C₃₃H₄₆N₂O₈; Mol. Wt.: 598.73

Example 2

Synthesis of Compound-2

To a two-necked 500 mL flask were added compound 1 (50 mmol),2,2-dimethoxypropane (200 mmol), and anhydrous toluene (20 vol). Oneneck of the flask was fitted with a Soxhlet extractor, the thimble ofwhich was filled with granular anhydrous CaCl₂ (75 g) to trap MeOH andH₂O. The other neck of the flask was sealed with a septum for sampling.After the system was flushed with argon for 5 min and then heated toreflux for 5 min, p-toluenesulfonic acid monohydrate (430 mg, 4.5 mol %)was added and left refluxing for 12 h. Reaction mixture concentratedunder reduced pressure. The reaction residue diluted with ethyl acetate(10 Vol), washed with saturated sodium bi carbonate solution followed bybrine. The organic layer dried over sodium sulfate, filtered andconcentrated under vacuum yielded compound 2. M.F: C₁₆H₂₂N₂O₄; Mol. Wt.:306.36.

Synthesis of Compound-4

Compound 2 (1.0 mmol) and 2,4-dimethoxy benzyl aldehyde 3 (1.0 mmol)taken in 1,2 Dichloromethane (20 vol; LR grade) & stirred for 2 h atroom temperature for imine formation, then sodium triacetoxy borohydride(1.5 mmol) was added at 0° C. and the reaction mixture was allowed tostir for 4-6 h at rt. On completion of the reaction (monitored by TLC),the reaction mixture was diluted with DCM (50 vol), washed with water(50 vol) followed by brine solution (50 vol), dried over anhydrousNa₂SO₄ and evaporated under reduced pressure to get crude product asviscous oil which was purified by column chromatography over neutralalumina by using 30% ethyl acetate-pet ether as eluent yielded 80% ofcompound 4 as a pale yellow liquid. M.F: C₂₅H₃₂N₂O₆; Mol. Wt.: 456.53

Synthesis of Compound-6

To a solution of compound 4 (1.0 mmol) in dry DCM (1.8 L) was added N,N-diisopropylethylamine (2.0 mmol) at −10° C., followed by drop wiseaddition of 1-chloroethylchloroformate (1.2 mmol) for 30 min at the sametemperature and the reaction mixture was allowed to stir for 1 h at 0°C. On completion of the reaction (monitored by TLC), the reactionmixture with intermediate 5 was directly used for the next step withoutfurther isolation and purification. In another RB flask the cis-5, 8,11, 14, 17-Eicosapentaenoic acid 6 (1.2 mmol) & anhydrous K₂CO₃ (3.0mmol) was taken in dry DMF (10 vol) stir at room temperature for 2 h andthen cooled to −10° C., intermediate 5 was added slowly drop wise over30 min. & then was allowed to stir at room temperature for 12 h.Reaction was monitored by TLC. On completion of the reaction, thereaction mixture was poured into water (100 mL) and extracted withdiethyl ether (2×1 L). The combined organic layers were washed withwater (2×500 mL) followed by brine solution (100 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure. The crude waspurified by column chromatography over 100-200 mesh silica gel by using0 to 20% ethyl acetate in pet ether as an eluent yielded 40% of compound7 as a yellow liquid. M.F: C₄₈H₆₄N₂O₁₀; Mol. Wt.: 829.03

Synthesis of Compound-7

25% TFA in DCM was added to compound 6 (1.0 mmol) at 0° C. and thereaction mixture was allowed to stir for 30 min at the same temperature.Reaction was monitored by TLC. On completion of the reaction, thereaction mixture was basified with saturated Na₂CO₃ solution (20 vol)and extracted with DCM (20 vol), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure. The crude was purified by columnchromatography over neutral alumina (Merck) by using 30% ethylacetate-pet ether as eluent yielded 46% of compound 7 as a pale yellowgummy solid. M.F: C₃₃H₄₆N₂O₈; Mol. Wt.: 598.73

Example 3

Synthesis of Compound-2

To a solution of compound 1 (50 mmol) in Dichloromethane (10 mL),Diisopropyl ethylamine (150 mmol) and methoxy ethoxy methyl chloride(MEM-Cl) (110 mmol) were added consecutively at 0° C. The reactionmixture stirred for 3.0 h, the completion of reaction mixture monitoredTLC & it is washed with water (10 Vol) & brine. The organic phase wasdried (Na2SO4) and evaporated under reduced pressure formed benzaldehydederivative 2. M.F: C₁₉H₃₀O₁₀; Mol. Wt.: 418.44.

Synthesis of Compound-3

Soxhlet extractor was filled with 20 g of molecular sieve withbenzaldehyde derivative (5 mmol) and hydrazine hydrate (75 mmol) wererefluxed overnight in (10 vol) of ethanol (16-24 h). The hot alcoholicsolution was filtered, and evaporation of solvent yielded (73%) of crudeproduct-3. After one recrystallization from ethanol yielded compound 3.M.F: C₁₉H₃₂N₂O₉; Mol. Wt.: 432.47.

Synthesis of Compound-5

To a stirred solution of compound 3 (1 mmol) and Compound 4 (1.0 mmol)in DCM (20 vol), EDCI.HCl (1 mmol) and DMAP (1.2 mmpl) were added atroom temperature and the reaction mixture was allowed to stir for 12 hat rt. Reaction was monitored by TLC. On completion of the reaction, thereaction mixture was diluted with DCM (50 vol), washed with water (50vol) followed by brine solution (20 vol) and dried over anhydrous Na₂SO₄and evaporated under reduced pressure. The crude was purified by columnchromatography over 100-200 mesh silica gel by using 40% ethylacetate-hexane as eluent yielded (70%) of compound 5. M.F: C₃₁H₄₅N₃O₁₃;Mol. Wt.: 667.7.

Synthesis of Compound-8

To a solution of compound 5 (1.0 mmol) in dry DCM (10 vol) was added N,N-diisopropylethylamine (2.0 mmol) at −10° C., followed by drop wiseaddition of 1-chloroethylchloroformate (1.2 mmol) for 30 min at the sametemperature and the reaction mixture was allowed to stir for 1 h at 0°C. On completion of the reaction (monitored by TLC), the reactionmixture intermediate 6 was directly used for the next step withoutfurther isolation and purification. In another RB flask the cis-5, 8,11, 14, 17-Eicosapentaenoic acid 7 (1.2 mmol) & anhydrous K₂CO₃ (3.0mmol) was taken in dry DMF (10 vol) stir at room temperature for 2 h andthen cooled to −10° C., intermediate 6 was added slowly drop wise over30 min. & then was allowed to stir at room temperature for 12 h.Reaction was monitored by TLC. On completion of the reaction, thereaction mixture was poured into water (100 mL) and extracted withdiethyl ether (2×1 L). The combined organic layers were washed withwater (2×500 mL) followed by brine solution (100 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure. The crude waspurified by column chromatography over 100-200 mesh silica gel by using0 to 20% ethyl acetate in pet ether as an eluent yielded 40% of compound8 as a yellow liquid. M.F: C₄₆H₆₆N₂O₁₂; Mol. Wt.: 839.02

Synthesis of Compound-9

25% TFA in DCM was added to compound 8 (1.0 mmol) at 0° C. and thereaction mixture was allowed to stir for 30 min at the same temperature.Reaction was monitored by TLC. On completion of the reaction, thereaction mixture was basified with saturated Na₂CO₃ solution (20 vol)and extracted with DCM (20 vol), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure. The crude was purified by columnchromatography over neutral alumina (Merck) by using 30% ethylacetate-pet ether as eluent yielded 46% of compound 9 as a pale yellowgummy solid. M.F: C₃₃H₄₇N₃O₉; Mol. Wt.: 629.74

The term “sample” refers to a sample of a body fluid, to a sample ofseparated cells or to a sample from a tissue or an organ. Samples ofbody fluids can be obtained by well known techniques and include,preferably, samples of blood, plasma, serum, or urine, more preferably,samples of blood, plasma or serum. Tissue or organ samples may beobtained from any tissue or organ by, e.g., biopsy. Separated cells maybe obtained from the body fluids or the tissues or organs by separatingtechniques such as centrifugation or cell sorting. Preferably, cell-,tissue- or organ samples are obtained from those cells, tissues ororgans which express or produce the peptides referred to herein.

EQUIVALENTS

The present disclosure provides among other things compositions andmethods for treating metabolic conditions or neurodegenerative disordersand their complications. While specific embodiments of the subjectdisclosure have been discussed, the above specification is illustrativeand not restrictive. Many variations of the systems and methods hereinwill become apparent to those skilled in the art upon review of thisspecification. The full scope of the claimed systems and methods shouldbe determined by reference to the claims, along with their full scope ofequivalents, and the specification, along with such variations.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those itemslisted above, are hereby incorporated by reference in their entirety asif each individual publication or patent was specifically andindividually indicated to be incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

What is claimed is:
 1. A compound represented by:


2. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 3. The pharmaceutical compositionof claim 2, wherein said pharmaceutical composition is formulated foruse by oral administration, delayed release or sustained release,transmucosal administration, syrup, topical administration, parenteraladministration, injection, subdermal administration, oral solution,rectal administration, buccal administration or transdermaladministration.
 4. The pharmaceutical composition of claim 3, whereinsaid compounds and compositions are formulated for the treatment ormanagement of neuromuscular and neurodegenerative disorders, whereinsaid neuromuscular and neurodegenerative disorders are Parkinson'sdisease, scleroderma, restless leg syndrome, hypertension or gestationalhypertension.